tbuckley/cabot-search huggingface dataset:
Examining safety and durable disease remission in R/R B-ALL after autologous CD19-directed CAR T cells produced by novel PRIMCAR manufacture platform.
Authors: Zhi Yang, Shiqi Li, Yu Li, Lin Liu, Zhongtao Yuan, Yingzi Zhang, Le Luo, Lihua Zhang, Yingnian Chen, Qianzhen Zhang, Junjie Shen, Yunyan Li, Linling Wang, Meiling Wang, Wei Zhu, Xiao He, Youcheng Wang, Yancheng Dong, Sanbin Wang, Cheng Qian
Journal: Journal of Clinical Oncology (2023)

7026 Background: CD19 chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy in the r/r B-ALL. However, the life-threatening side effect and disease relapse limited its wide application. To overcome these limitations, we established a novel PrimeCAR platform (PRIMCAR) and reported the preliminary safety and effectiveness data of MC-1-50 CAR-T cells before (Shiqi Li, et al. J Clin Oncol 2022; 40 [suppl 16]. Abstract 7008). Here, we present updated data. Methods: In this Phase I /II study (NCT04271410), MC-1-50 CAR T cells were manufactured by the PRIMCAR platform, which reduces manufacture periods to about 2 days. Patients (pts) received single-dose of MC-1-50 at dose ranged 1-5×10 5 CAR+/kg (Level 1, 1×10 5 CAR+/kg; Level 2, 2×10 5 CAR+/kg; Level 3, 3×10 5 CAR+/kg; Level 4, 5×10 5 CAR+/kg). Pts were pre-conditioned with fludarabine (25-30 mg/m 2 ) and cyclophosphamide (200-300 mg/m 2 ) daily for 3 days. Toxicity was graded by CTCAE, CRS and ICANS were graded by ASTCT criteria. Results: 19 pts with r/r B-ALL were infused. Disease characteristics and outcomes are shown in the table. No DLTs were reported. 18 pts (94.7%) experienced CRS, including 10 (52.6%) at grade 1, 7 (36.8%) at grade 2, 1 (5.3%) at grade 3, and no ≥ 4 CRS were observed. Three pts (15.8%) experienced ICANS, including 2 (10.5%) at grade 1, 1(5.3%) at grade 2, and no ≥ 3 ICANS occurred. All patients achieved CR/CRi (BM MRD-) in the first month. All patients received no other anti-tumor therapy until relapse was confirmed. The median DOR was not reached. 6 patients confirmed relapse, including 4 were CD19 negative and 2 were CD19 positive but with CD19 gene mutation at the time of relapse. All patients in 4 dose levels had good CAR-T expansion and exhibited long persistence features. Only 3 patients experienced the loss of CAR-T. Conclusions: Treatment of r/r B-ALL at a very low dose resulted in excellent safety profiles while exhibiting a high and durable efficacy. That makes this PRIMCAR platform potential for outpatient administration in the future. Clinical trial information: NCT04271410 . [Table: see text]
Preliminary data of a phase 1b/2 study of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).
Authors: Sikander Ailawadhi, Masa Lasica, Chengcheng Fu, Sheeba K. Thomas, Depei Wu, Shuhua Yi, Tanya Siddiqi, Qingsong Yin, John N. Allan, Wenming Chen, Jeffrey V Matous, Ru Feng, Zi Chen, Min Yu, Mingyu Li, Zicong He, Mohammad Ahmad, Hengbang Wang, Asher Alban Akmal Chanan-Khan, Yifan Zhai
Journal: Journal of Clinical Oncology (2023)

7569 Background: B-cell lymphoma 2 inhibitors (BCL-2i) are well tolerated and effective in treating B-cell lymphoproliferative disorders such as CLL. Investigational agent lisaftoclax is a novel, oral, highly selective and potent BCL-2i. Preclinical data show a strong synergistic effect of lisaftoclax plus ibrutinib in an ibrutinib-insensitive PDXWM1 model. Methods: This global, open-label, multicenter study evaluates the safety and efficacy of lisaftoclax alone and combined with ibrutinib or rituximab in pts with WM. Pts were enrolled in 3 arms: Arm A (lisaftoclax), BTKi-resistant/intolerant pts; Arm B (lisaftoclax plus ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax plus rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high TLS risk. Primary objectives were pharmacokinetics (PK), safety, and efficacy assessments; responses were assessed per IWWM criteria. Results: As of January 25, 2023, 46 pts were enrolled (Arm A [n = 14]; up to 1,000 mg; Arm B [n = 24]; up to 1,200 mg; Arm C [n = 8]; up to 800 mg). Baseline characteristics are shown in the table. Median (range) treatment duration was 6 (1-18; Arm A), 14 (1-27; B), and 8 (2-26; C) months. Overall response rates (ORRs) were: Arm A, 25% (median time to response [MTTR], 4.3 months); Arm B, 90.9% (MTTR, 1.9); Arm C, 37.5% (MTTR, 4.4). No significant difference was observed between pts with and without CXCR4-mut. At 1,200 mg, 1 DLT (grade 3 clinical TLS), due to pre-existing renal impairment, was reported. At 1,000 mg, 1 grade 3 laboratory TLS occurred in Arm B because of dehydration and active symptomatic therapies; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (13%), leukocytopenia (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmias were not observed. Only 1 pt required dose reduction (due to neutropenia). MTD has not been reached. A total of 14 pts discontinued study treatment because of disease progression (n = 5) and AE (n = 1). Lisaftoclax plus ibrutinib showed a PK exposure comparable to ibrutinib alone, indicating no potential DDI. Conclusions: Lisaftoclax alone or combined with ibrutinib/rituximab demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. Internal study identifier: APG2575WU101. *SA and ML are co-first authors. Clinical trial information: NCT04260217 . [Table: see text]
Recruitment lessons learned from a cross-sectional study of quality of life experienced by people receiving treatments for hepatocellular carcinoma.
Authors: Christopher D. Woodrell, Deborah Watman, Sasha Perez, Sara Lubetsky, Yingtong Chen
Journal: Journal of Clinical Oncology (2023)

e24162 Background: People with advanced-stage hepatocellular carcinoma (HCC) are living longer given improved treatment effectiveness, yet we know little of their unmet palliative and supportive care needs. Previous studies of palliative care in populations of people facing liver diseases and liver cancer have cited difficulty with recruitment. Methods: This is a cross-sectional study at a single academic medical center. Participants are recruited from a multi-specialty liver cancer practice that includes surgery, interventional radiology, and medical and radiation oncology. Treating physicians identify appropriate participants from a list of pre-screened eligible individuals generated by the study team. Once enrolled validated survey instruments are used to collect data at two time points separated by one month and a qualitative interview is conducted that focuses on the experience of living with HCC. PDSA framework was used to improve recruitment procedures to a rate of 3-4 per month. Results: During the first four months we identified 19 potential participants. Of these, ten were ineligible: four did not meet timing criteria (enrollment before treatment initiation); three lacked English proficiency; and three were identified by their physician as not appropriate for the study. Of the remaining nine potential participants, four were unable to be contacted by phone, two were uninterested (including one who specifically ended the call after hearing the term palliative care), one was lost to follow-up, and two were consented and enrolled. In response, the following modifications were made to the protocol: (1) Medical eligibility criteria were liberalized so that enrollment could occur at any time during treatment; (2) a protocol to involve trained interpreters (in-person when possible) was implemented and a study team member who can conduct qualitative interviews in Spanish was added; (3) the title of the study was changed to more accurately focus on understanding quality of life (from “Palliative Care for People Facing HCC”) to address patient and physician concern; and (4) recruitment efforts are now focused on in-person introduction of the study to develop rapport. Since implementation of these changes, enrollment doubled in just one month. Conclusions: We identified actionable protocol modifications to increase study enrollment. Liberalized inclusion criteria, language inclusivity, and careful attention to stigma around palliative care may be generalizable to similar studies about supportive care, palliative care, and hospice in the population of people facing liver cancer. Additionally, avoiding language-based exclusions for lack of resources (rather than scientific ones) increases inclusivity in research and will allow for a more meaningful and accurate description of all our participants’ needs.
Transcriptional metabolic profiling young onset colorectal cancer (CRC) patients.
Authors: Deepak Vadehra, Spencer Rosario, Jianmin Wang, Yali Zhang, Hua-Hsin Hsiao, Jill Kolesar, Patricia McDonald, Daniel Spakowicz, Sami Ibrahimi, Fred Tabung, Dwight Hall Owen, Sarbajit Mukherjee
Journal: Journal of Clinical Oncology (2023)

3509 Background: Patients diagnosed with colorectal cancer (CRC) at age &lt; 50 years typically present with more advanced disease, resulting in poor therapeutic response and clinical outcomes. Therefore, there is an unmet need to understand the differences in transcriptional profiles between younger (&lt;50) and older ( &gt; 50) CRC patients. Methods: Using TCGA (n = 397; &gt; 50 = 349; &lt; 50 = 48) and Oncology Research Information Exchange network (ORIEN) CRC datasets (n = 460; &gt; 50 = 364 ; &lt; 50 = 96), patients were separated into younger and older populations. Baseline characteristics of the patients in this analysis are provided in the accompanying table. Subsequently, their transcriptional profiles were compared and assessed via differential gene expression analysis (DESeq2), gene set enrichment analysis (GSEA), immune deconvolution (TIMER2.0), and metabolic pathway analysis (MetaPhOR). These pathways were then mapped to assess transcriptional dysregulation, and patterns of predicted metabolic flux. Results: Comparisons of older and younger groups revealed a large number of significantly differentially expressed transcripts (n = 2629), enrichment in younger groups of metabolic pathways (amino acids and lipids), oncogenes (MYC targets and NRAS targets), and cellular processes. In the older group we found enrichment of methylation and histone modification, immune response, and other metabolic pathways, like androgens. Metabolic pathway analysis revealed consistent alterations in steroid hormone metabolism and kynurenine metabolism, which were largely upregulated in the over 50 group. Additionally, pathways associated with response to both CTLA4 and PDL1 treatment were largely upregulated in the over 50 group. This transcriptional signature may be associated with a pre-disposition to different clinical outcomes and therapeutic response for agents targeting these pathways. Conclusions: Overall, this study has revealed differences in transcriptional metabolic profiles and other drivers of disease, as well as immune profiles, between younger and older CRC populations. This biology should be explored in the future, as new avenues for treatment in younger CRC populations. [Table: see text]
Does severity of periodontal disease influence the risk of developing gastrointestinal malignancies?
Authors: Umar Iqbal, Poliana Mendes Duarte, William D. Duncan, Zhanna Galochkina, Zhongyue Zhang, Stephen H Kostewicz, Manuel E Borobia, Ji-Hyun Lee, Sherise C. Rogers
Journal: Journal of Clinical Oncology (2023)

e15549 Background: In recent years, multiple observational studies have suggested increased risk of developing gastrointestinal (GI) malignancies in patients with prior periodontal disease (PD). Our aim was to determine whether a difference in incidence of GI malignancies exists amongst patients with pre-existing mild-moderate vs. severe PD. Methods: This was a single institution retrospective IRB approved study. We identified a cohort of patients between 2011-21 with PD and concurrent registration in independent dental and medical electronic health record systems at the University of Florida. Patients were stratified into 2 groups based on severity of PD (mild-moderate or severe). Descriptive statistics were used to compare the 2 groups based on demographics and medical history. Cumulative incidence curves were used to compare GI malignancy incidence between the 2 groups. Multivariable logistic regression was used to identify predictors of developing GI malignancies. Results: A total of 2168 patients with PD were identified with a median follow up of 4.7 (IQR 2.6-6.8) yr. Of these, 54% had severe PD and 46% had mild-moderate PD. Severe PD was more common within males (58% vs 50% in females), Black race (62% vs 52% in Caucasians), diabetics (59% vs 52% in non-diabetics), cigarette smokers (60% vs 51% in non-smokers) and excessive alcohol intake (70% vs 61% in moderate alcohol intake). There was no significant difference in cumulative incidence rates of GI malignancies (colon, pancreatic, gastric, hepatic, and esophageal) between the PD groups stratified by severity (12% in severe vs 11% in mild-moderate, p = 0.6 at 5 yr follow up). In univariable logistic regression, severe vs mild-moderate PD OR was 1.12 [95% CI: 0.87,1.46], thus more severe form of PD is not associated with developing a GI malignancy. In multivariable logistic regression, severe vs mild/moderate PD adjusted OR was 1.04 [95% CI: 0.79,1.36], thus also not statistically significant, with other risk factors of developing GI malignancies identified in Table 1. Conclusions: There was no association between the severity of periodontal disease and subsequent development of GI malignancy. [Table: see text]
Evaluation of microsatellite instability status, a definitive predictive biomarker for immune checkpoint inhibitors (ICI), in underrepresented minorities (URM) with gastrointestinal (GI) cancers.
Authors: Fiyinfolu Balogun, Mirella Altoe, Catherine O'Connor, Nobel Chowdhury, Andrea Cercek, Choong-kun Lee, Michael Bonner Foote, Daehee Kim, Steven Brad Maron, Dae Won Kim, Karyn Ronski, Joon Oh Park, Calvin Y. Chao, Yelena Y. Janjigian, Ghassan K. Abou-Alfa, Luis A. Diaz, Eileen Mary O'Reilly, Francisco Sanchez-Vega, Debyani Chakravarty, Wungki Park
Journal: Journal of Clinical Oncology (2023)

3538 Background: Mismatch repair deficiency (dMMR) results in MSI-H state and is the first tumor type-agnostic biomarker predictive of ICI response. Among GI cancers, MSI-H is most frequent in colorectal cancer (CRC 15%), gastroesophageal (GEC, 5%) and other (small bowel, hepatopancreatobiliary; 1%). For CRC, MSI-H can be attributed to germline mutation (Lynch syndrome, 3%) or somatic inactivation (sporadic, 12%) of foundational MMR genes. Studies evaluating ICI efficacy in dMMR cancers focus primarily on non-Hispanic White (NHW) patients (pts). We present prevalence, tumor genomic features, and outcomes in pts from a large cohort at Memorial Sloan Kettering (MSK). Methods: Retrospective analysis of MSI-H GI cancers from MSK-IMPACT database. Pts were grouped by self-reported race and ethnicity into 4 study arms: NHW, Asian, non-Hispanic Black (NHB), and Hispanic. Age, tumor type, tumor mutation burden (TMB), and MMR genes were analyzed. Overall survival (OS) estimated with Kaplan-Meier. Results: Of 776 pts with MSI-H GI cancers: 623 (80.3 %) NHW, 60 (7.7 %) Hispanic, 50 Asian (6.5 %), and 43 (5.5 %) NHB. CRC (76%), GEC (14%), other cancers (10%). We present initial evaluation of CRC and GEC: Median age, TMB, and most frequently altered MMR genes (MMR gene FA) are in table. Median OS (mOS) in NHW/URM by receipt of ICI in MSI-H CRC were 38.5m/25.3m (p 0.07) in no-ICI group, 34.2m/28.7m (p 0.64) in +ICI group; MSI-H GEC 43.4m/30m (p 0.44) in no-ICI group, 28.8m/26.7m in +ICI group. Conclusions: Number of URM MSI-H CRC/GEC pts is 7 to 15-fold less than NHW, with no such difference in % MSI-H/MSS between groups; reflecting significant undertesting in URM pts. In MSI-H CRC, median age (m-Age) at sequencing was younger in URM compared to NHW; pronounced in Asian and Hispanic patients, who were 10+ years younger than NHW. No such age difference seen in GEC. No difference in mOS detected between NHW and URM, however a non-significant trend towards worse mOS in URM was observed in the no-ICI group. Next steps include validation of clinico-genomics of MSI-H GI cancers in other large cohorts, including TEMPUS (N = 768) which is ongoing. [Table: see text]
Nominating molecular/immunologic drivers of central nervous system (CNS) metastases in squamous cell carcinoma of the head/neck (SCCHN).
Authors: Alec Kacew, Michael Wotman, Charles T Quinn, Laura E MacConaill, Ann Marie Egloff, Stephanie M Jones, Kathleen L. Pfaff, Scott J. Rodig, Kartik Sehgal, Robert I. Haddad, Marshall R. Posner, Glenn J. Hanna
Journal: Journal of Clinical Oncology (2023)

e18002 Background: In the ~1% of patients with SCCHN who experience CNS metastases, median overall survival (mOS) is &lt;1 year. We investigated whether molecular/immunologic features distinguish SCCHN cases that metastasize to the CNS. Methods: We performed a case-control study on a convenience sample of individuals with SCCHN treated at two academic institutions. Next generation targeted sequencing and/or immunoprofiling of primary and metastatic tumor sites were performed. Results: We identified 39 patients with SCCHN (21 with CNS metastases (cases), 18 without (controls)). Median age at diagnosis 60, 79% male, 46% current/former smokers, 51% oropharyngeal primary, 51% HPV+/31% HPV-/18% not tested (NT) across all cases, and 69% stage III or IV disease at diagnosis. HPV+ frequency trended higher among cases (52%+, 14%-, 33% NT) vs. controls (50%+, 50%-, 0% NT) (p=0.08). mOS from diagnosis was 34.4 months (95% CI 14.5-41.0) in cases and 44.4 months (95% CI 19.0-82.3) in controls. Genomic data was available for 18 (86%) cases and 12 (67%) controls. Most common mutations in cases were KMT2D (39%) and NOTCH1 (39%). There were no genes for which alteration frequency differed significantly between groups. Tumors of 18 (86%) cases and 18 (100%) controls underwent immunoprofiling. Mean PD-1 density at the tumor-stroma interface (TSI), CPS, and TPS were higher in controls (Table). In cases, TSI PD-1 density tended to be higher at primary sites than at sites of CNS metastases. No significant difference was seen in CD8 or FOXP3 staining. Conclusions: SCCHN with CNS metastases shows markers of lower immunogenicity at both the primary site and site of CNS metastasis vs. other SCCHN tumors, regardless of HPV status. This suggests that localized tumors with low immune infiltration and poor responsiveness to immunotherapy may be at higher risk of CNS metastasis and could imply reduced benefit from immunotherapy for patients with CNS metastases. [Table: see text]
Pan-cancer analysis and KNSTRN as a potential prognosis biomarker.
Authors: Shanshan Xiao, Yuqing Zou, Li Wang, Qian Wang, Tao Wang
Journal: Journal of Clinical Oncology (2023)

e15180 Background: KNSTRN (Kinetochore-Localized Astrin-Binding) protein participates in the biological processes of chromosome alignment and segregation and is required for accurate mitosis. However, only a few researches have focused on the functional roles of KNSTRN in various cancers. Pan-cancer analysis facilitates better understanding the KNSTRN functions in tumor development and progression. Methods: In this study, RNA-Seq data of the tumor and the adjacent tissue, along with the patient information, were collected from 30 solid tumor types in TCGA database. For each tumor type, the tumor samples were stratified into High_KNSTRN (HK) or Low_KNSTRN (LK) based on the threshold of median KNSTRN expression. As an important prognostic biomarker in pan cancers, tumor mutation burdens (TMB) were evaluated between HK and LK groups. Highly and unqiuely expressed genes in each group were included for functional enrichment analysis. To further investigate the prognostic value of KNSTRN, Kaplan-Meier survival analyses were carried out based on the overall survival (OS) data. Moreover, the mutation types such as SNV, indel, CNV, and rearrangement ooccured in those tumor types were obtained from cBioPortal of Cancer Genomics platform. We also used TIMER2 database to evaluate the associations between KNSTRN expression and CAFs and CD8+ T cells infiltrating levels. Results: We found KNSTRN was significantly up-regulated in 20 cancer types and significantly down-regulated in THCA. Consistent with the previous studies, higher KNSTRN expression levels were significantly associated with shorter OS in most cancers. The most frequently detected mutations were found in MESO, SKCM and UCS. The “deep deletion” CNV was the most frequently occurred type in MESO and UCS, and the SNV mutations highly occurred in SKCM, which meant the KNSTRN mutations were quite diverse across various cancer types. In addition, KNSTRN expression and TMB were positively correlated, and the higher TMB indicated worse prognoses in 13 cancers. Highly expressed genes in the LK group mainly participated in immune response and a large family of environmental information processing pathways. Compared to highly expressed genes related pathways in HK group, KNSTRN may likely be involved in pro-tumor regulator pathways. Moreover, KNSTRN was positively correlated with immunosuppressive genes and CAFs cell infiltration levels but negatively correlated to CD8+ T cells in most cancers. Conclusions: Most of the cancers had up-regulated KNSTRN expressions compared with adjacent tissues. Higher KNSTRN expression was significantly associated with worse clinical outcomes in those cancers. Comprehensive downstream analysis revealed the underlying mechanism of KNSTRN in tumor development and its potential clinical value as a prognostic biomarker.